Dementia results from a wide variety of distinctive pathological processes. The most common pathological processes causing dementia are Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA) and prion-mediated diseases (see, e.g., Haan et al. Clin. Neurol. Neurosurg. 1990, 92 (4):305-310; Glenner et al. J Neurol. Sci. 1989, 94:1-28). AD affects nearly half of all people past the age of 85, the most rapidly growing portion of the United States population. As such, the number of AD patients in the United States is expected to increase from about 4 million to about 14 million by the middle of the next century.
Treatment of AD typically is the support provided by a family member in attendance. Stimulated memory exercises on a regular basis have been shown to slow, but not stop, memory loss. A few drugs, for example Aricep™, provide treatment of AD.
A hallmark of AD is the accumulation in the brain of extracellular insoluble deposits called amyloid plaques and abnormal lesions within neuronal cells called neurofibrillary tangles. Increased plaque formation is associated with an increased risk of AD. Indeed, the presence of amyloid plaques, together with neurofibrillary tangles, are the basis for definitive pathological diagnosis of AD.
The major components of amyloid plaques are the amyloid Aβ-peptides, also called Aβ-peptides, which consist of three proteins having 40, 42 or 43 amino acids, designated as the Aβ1-40, Aβ1-42, and Aβ1-43 peptides, respectively. The Aβ-peptides are thought to cause nerve cell destruction, in part, because they are toxic to neurons in vitro and in vivo.
The Aβ peptides are derived from larger β-amyloid precursor proteins (APP proteins), which consist of four proteins containing 695, 714, 751 or 771 amino acids, designated as the APP695, APP714, APP751 and APP771, respectively. Proteases are believed to produce the Aβ peptides by cleaving specific amino acid sequences within the various APP proteins. The proteases are named “secretases” because the Aβ-peptides they produce are secreted by cells into the extracellular environment. These secretases are each named according to the cleavage(s) they make to produce the Aβ-peptides. APP is cleaved by alpha- and beta-secretases, causing the release of soluble derivatives of protein ((α-APPs and β-APPs) and the retention of membrane-bound 83- and 99-amino acid fragments (C83 and C99). These fragments are substrates for the enzyme gamma-secretase. Gamma-secretase produces the Aβ-peptide fragment from C99 and p3 from C83. Gamma-secretase and beta-secretase inhibitors are thus expected to inhibit the production of Aβ-peptide. (Haass, C. and Selkoe, D. J. 1993 Cell 75:1039-1042; Selkoe, D. J. et. al. Annu. Rev. Cell Biol. 10, 373-403 (1994); Wolfe, M. S. et. al., Nature, 398, 513).
This invention relates to novel compounds that inhibit Aβ-peptide production, to pharmaceutical compositions comprising such compounds, and to methods of using such compounds to treat neuorodegenerative disorders.